title: Membrane lipid saturation activates IRE1α without inducing clustering.
abstract: The unfolded protein response (UPR) is an adaptive stress response that responds to the accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) and that adjusts the protein-folding capacity to the needs of the cell. Perturbation of cellular lipids also activates the UPR. Lipid-induced UPR has attracted much attention because it is associated with the pathology of some metabolic diseases. However, how the lipid-induced UPR is activated remains unclear. We previously showed that palmitic acid treatment or knockdown of stearoyl-CoA desaturase in HeLa cells promotes membrane lipid saturation and activates the UPR. In this study, we compared UPR activation by membrane lipid saturation with UPR activation by conventional ER stressors that cause the accumulation of unfolded proteins such as tunicamycin and thapsigargin. Membrane lipid saturation induced autophosphorylation of inositol-requiring 1α (IRE1α) and protein kinase RNA-like ER kinase, but not the conversion of activating transcription factor-6α to the active form. A conventional ER stressor induced clustering of fluorescently tagged IRE1α fusion protein, but palmitic acid treatment did not, suggesting that IRE1α was activated without large cluster formation by membrane lipid saturation. Together, these results suggest membrane lipid saturation, and unfolded proteins activate the UPR through different mechanisms.
authors.affiliation: Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Yuto
authors.initials: Y
authors.lastname: Kitai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ariyama
authors.forename: Nozomu
authors.initials: N
authors.lastname: Kono
authors.forename: Daisuke
authors.initials: D
authors.lastname: Oikawa
authors.forename: Takao
authors.initials: T
authors.lastname: Iwawaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008563:Membrane Lipids / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D019308:Palmitic Acid / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D058767:Protein Unfolding / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D008563:Membrane Lipids; D008565:Membrane Proteins; D014415:Tunicamycin; D019308:Palmitic Acid; D019284:Thapsigargin; C403982:ERN2 protein, human; C460640:EIF2AK3 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases